1. Field of the Invention
This invention concerns new ruthenium hydride complexes, procedures of preparing alcohol compounds using these new complexes, and methods of separating racemic carbonyl compounds using these new complexes.
2. Description of the Prior Art
Since priorly, various methods have been known for preparing alcohol compounds by reduction of carbonyl compounds using ruthenium complexes as homogeneous catalysts. For example, in Japanese Unexamined Patent Publication No. Hei 11-189600, a ruthenium dichloride complex, having 2,2xe2x80x2-bis-(diphenylphosphino)-1,1xe2x80x2-binaphthyl, which has a C2 axis of symmetry and high chemical stability, as a phosphine ligand, is used as a chiral catalyst to reduce acetophenone under the presence of a strong base to obtain a corresponding alcohol at high enantiomeric excess and high yield.
However, since the reduction reaction using the abovementioned ruthenium dichloride complex as a chiral catalyst is carried out under the presence of a strong base, when a base-sensitive carbonyl compound having an ester group or xcex2-amino group, etc., is reduced, side reactions occur and an alcohol compound cannot be obtained efficiently.
An object of this invention is to provide ruthenium hydride complexes that enable efficient reduction of base-sensitive carbonyl compounds. Another object of this invention is to provide procedures of preparing alcohol compounds and methods of separating racemic carbonyl compounds using these ruthenium hydride complexes.
As a result of diligent research, the present inventors have found compounds of general formula (1) to be ruthenium hydride complexes that function as catalysts that enable reduction of carbonyl compounds without the presence of a strong base. In the present specification, a compound of general formula (1) is not restricted to a single diastereomer and may be a cis form or a trans form. 
(wherein for R1R2Pxe2x80x94Wxe2x80x94PR3R4, W is a binaphthyl group, which is bonded to phosphorus atoms at positions 2 and 2xe2x80x2 and may have one or more substituents at any of the other positions, each of R1 to R4 is the same or different hydrocarbon group that may or may not have one or more substituents, R1 and R2 may together form a carbon chain ring that may have one or more substituents, R3 and R4 may together form a carbon chain ring that may have one or more substituents,
each of R5 to R8 is the same or different hydrocarbon group that may or may not have one or more substituents,
Z is a hydrocarbon group that may or may not have one or more substituents, and
each of the ligands of Ru may be positioned in any manner).
Unlike prior-art ruthenium dihalide complexes, ruthenium hydride complexes of general formula (1) enable carbonyl compounds to be reduced without the presence of a strong base and thus enable alcohol compounds to be prepared by efficient reduction of base-sensitive carbonyl compounds.
Each of the hydrocarbon groups at R1 to R4 of general formula (1) may have a substituent and may be an aliphatic or alicyclic hydrocarbon group that is saturated or unsaturated, amonocyclic or polycyclic aromatic or fatty aromatic hydrocarbon group, or any of various such hydrocarbon groups having substituents. Such a hydrocarbon group may be selected from the group consisting of such hydrocarbon groups as alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl, tolyl, xylyl, naphthyl, phenylalkyl, etc., and hydrocarbon groups with any of various allowable substituents, such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro, and cyano groups, etc. Also, when a ring is formed by R1 and R2 or by R3 and R4, R1 and R2 or R3 and R4 may be bonded to form a carbon chain and may be selected to have any of various allowable substituents, such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro, and cyano groups, etc., on the carbon chain.
Examples of the amine ligand (see,general formula (2)) in general formula (1) include ethylenediamine, 1,2-diaminopropane, 1,3-diaminopropane, 1,4-diaminobutane, 2,3-diaminobutane, 1,2-cyclopentanediamine, 1,2-cyclohexanediamine, N-methylethylenediamine, N,Nxe2x80x2-dimethylethylenediamine, N,N,Nxe2x80x2-trimethylethylenediamine, N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, o-phenylenediamine, p-phenylenediamine,etc. An optically active diamine compound may also be used. Examples include such optically active diamine compounds as optically active 1,2-diphenylethylenediamine, 1,2-cyclohexanediamine, 1,2-cycloheptanediamine, 2,3-dimethylbutanediamine, 1-methyl-2,2-diphenylethylenediamine, 1-isobutyl-2,2-diphenylethylenediamine, 1-isopropyl-2,2-diphenylethylenediamine, 1-methyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-isobutyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-isopropyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-benzyl-2,2-di(p-methoxyphenyl)ethylenediamine, 1-methyl-2,2-dinaphtylethylenediamine, 1-isobutyl-2,2-dinaphthlethylenediamine, 1-isopropyl-2,2-dinaphtylethylenediamine, etc. Furthermore, the optically active diamine compounds that may be used are not limited to optically active ethylenediamine derivatives, and optically active propanediamine derivatives, butanediamine derivatives, etc., may also be used. 
As a ruthenium complex that is to be the starting material for complex synthesis, a complex of valence, 0, 1, 2, 3 or higher valence may be used. When a zero-valent or univalent ruthenium complex is used, oxidation of ruthenium must be carried out by the final stage. When a divalent complex is used, the ruthenium complex and phosphine ligand and then the amine ligand may be reacted successively or in reverse order or simultaneously for synthesis. When a ruthenium complex with a valence of 3, 4, or greater is used as the starting material, reduction of ruthenium atom must be carried out by the final stage. A ruthenium complex indicated for example in Japanese Unexamined Patent Publication No. Hei 11-189600 may be used as the ruthenium complex that is to be the starting material, and specific examples include inorganic ruthenium compounds, such as ruthenium (III) chloride hydrate, ruthenium (III) bromide hydrate, ruthenium (III) iodide hydrate, etc., diene-liganded ruthenium compounds, such as [ruthenium dichloride(norbornadiene)] polynuclear complex, [ruthenium dichloride(cyclooctadiene)] polynuclear complex, etc., aromatic-compound-liganded ruthenium compounds, such as [ruthenium dichloride(benzene)] dinuclear complex, [ruthenium dichloride(p-cimene)] dinuclear complex, [ruthenium dichloride(trimethylbenzene)] dinuclear complex, [ruthenium dichloride(hexamethylbenzene)] dinuclear complex, etc., and phosphine-liganded complexes, such as dichlorotris(triphenylphosphine)ruthenium, etc.
The reaction of the ruthenium complex that is the starting material and a phosphine ligand is carried out in toluene, xylene, or other aromatic hydrocarbon solvent; pentane, hexane, or other aliphatic hydrocarbon solvent; methylene chloride or other halogen-containing hydrocarbon solvent; ether, tetrahydrofuran, or other ether solvent; methanol, ethanol, 2-propanol, butanol, benzyl alcohol, or other alcohol solvent; or acetonitrile, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO) or other organic solvent containing a heteroatom; at a reaction temperature between xe2x88x92100xc2x0 C. and 200xc2x0 C. to obtain a phosphine-ruthenium halide complex.
The reaction of the diamine-phosphine-ruthenium halide complex obtained and an amino ligand is carried out in toluene, xylene, or other aromatic hydrocarbon solvent; pentane, hexane, or other aliphatic hydrocarbon solvent; methylene chloride or other halogen-containing hydrocarbon solvent; ether, tetrahydrofuran, or other ether solvent; methanol, ethanol, 2-propanol, butanol, benzyl alcohol, or other alcohol solvent; or acetonitrile, DMA, DMF, N-methylpyrrolidone, DMSO or other organic solvent containing a heteroatom; at a reaction temperature between xe2x88x92100xc2x0 C. and 200xc2x0 C. to obtain a phosphine-ruthenium halide complex.
A ruthenium hydride complex expressed by general formula (1) can be obtained by subsequently hydrogenating the diamine-phosphine-ruthenium halide complex using a metal borohydride. For example, a ruthenium hydride complex expressed by general formula (1) can be obtained by reacting the diamine-phosphine-ruthenium halide complex with a metal borohydride, such as sodium borohydride, potassium borohydride, etc., in toluene, xylene, or other aromatic hydrocarbon solvent; pentane, hexane, or other aliphatic hydrocarbon solvent; methylene chloride or other halogen-containing hydrocarbon solvent; ether, tetrahydrofuran, or other ether solvent; methanol, ethanol, 2-propanol, butanol, benzyl alcohol, or other alcohol solvent; or acetonitrile, DMA, DMF, N-methylpyrrolidone, DMSO or other organic solvent containing a hetero atom; at a reaction temperature between xe2x88x92100xc2x0 C. and200xc2x0 C. A ruthenium hydride complex expressed by general formula (1) can also be obtained by first converting a phosphine-ruthenium halide complex to a phosphine-ruthenium hydride complex and then reacting with a diamine.
When a ruthenium hydride complex expressed by general formula (1) is to be used as a reduction catalyst, though the usage amount thereof will differ according to the reaction vessel and economy, it may be used at molar ratio S/C (S stands for substrate and C stands for catalyst), with respect to a carbonyl compound that is the reaction substrate, of 10 to 5000000 and preferably in the range of 500 to 10000. With a ruthenium hydride complex expressed by general formula (1), a carbonyl compound can be reduced to produce an alcohol compound without the need to add a base for reduction of the carbonyl compound and by mixing with a carbonyl compound under base-free conditions and thereafter applying hydrogen pressure or stirring under the presence of a hydrogen donor. Though this ruthenium hydride complex may be used as a reduction catalyst in isolated form, the ruthenium hydride complex may be as it is used without isolating after preparation, and, for example, the reduction reaction may be carried out in the reaction system used for preparation of the complex.
A suitable solvent may be used as a solvent for preparing an alcohol compound by reduction of a carbonyl compound using a ruthenium hydride complex expressed by general formula (1). Examples include toluene, xylene, or other aromatic hydrocarbon solvent; pentane, hexane, or other aliphatic hydrocarbon solvent; methylene chloride or other halogen-containing hydrocarbon solvent; ether, tetrahydrofuran, or other ether solvent; methanol, ethanol, 2-propanol, butanol, benzyl alcohol, or other alcohol solvent; or acetonitrile, DMA, DMF, N-methylpyrrolidone, DMSO or other organic solvent containing a heteroatom; or a mixed solvent of the above. Here, since the reaction product is an alcohol compound, an alcohol solvent is preferable as the reaction solvent, and among alcohols, a secondary alcohol, such as 2-propanol, is especially preferable. The reduction reaction may also be carried out under solvent-free conditions.
Though a hydrogen pressure of 0.5 atm is sufficient for the reduction reaction as the present catalyst system is extremely high in activity, in view of economy, the hydrogen pressure should be set in the range of 1 to 200 atm and preferably in the range of 3 to 100 atm, and even if the pressure is set to 50 atm or less in view of the economy of the entire process, a high activity can be maintained. Though the reaction temperature is preferably set in the range of 15xc2x0 C. to 100xc2x0 C., in view of economy, the reaction may be carried out a temperature near room temperature of 20 to 45xc2x0 C. The reduction reaction will however proceed even at a low temperature of xe2x88x9230 to 0xc2x0 C. The reaction time will differ according to the reaction substrate concentration, temperature, pressure, and other reaction conditions, and the reaction will be complete in a few minutes to a few days. In terms of the form of reaction, the reduction reaction may be carried out in batch form or in continuous form.
A complex, among the ruthenium hydride complexes expressed by general formula (1), with which the phosphine ligand is an R form, enables preparation of an optically active alcohol compound by chiral reduction of an asymmetric carbonyl compound in a reaction solvent under the non-presence of a strong base and the presence of hydrogen or hydrogen donating compound. Here, the amine ligand is preferably an optically active diamine. In this case, though the chiral center carbon of the amine ligand may be an R, R form or an S, S form, or both forms may coexist (for example as a racemic mixture), an R, R form or an S, S form is preferable. The use of either an amine ligand of an R, R form or an S, S form is preferably selected in accordance with the type of asymmetric carbonyl compound that is the reaction substrate. That is, depending on the type of asymmetric carbonyl compound more favorable results may be obtained if the amine ligand is of an R, R form or more favorable results may be obtained if the amine ligand is of an S, S form, and it is thus preferable to select the steric structure of the amine ligand in accordance with the reaction substrate. A complex among the ruthenium hydride complexes expressed by general formula (1), with which the phosphine ligand is an S form, also enables preparation of an optically active alcohol compound by chiral reduction of an asymmetric carbonyl compound in a reaction solvent under the non-presence of a strong base and the presence of hydrogen or hydrogen donating compound. Here, the amine ligand is preferably an optically active diamine. In this case, though the chiral center carbon of the amine ligand may be an R, R form or an S, S form, or both forms may coexist (for example as a racemic mixture), an R, R form or an S, S form is preferable. The use of either an amine ligand of an R, R form or an S, S form is preferably selected in accordance with the type of asymmetric carbonyl compound that is the reaction substrate. That is, depending on the type of asymmetric carbonyl compound more favorable results may be obtained if the amine ligand is of an R, R form or more favorable results may be obtained if the amine ligand is of an S, S form, and it is thus preferable to select the steric structure of the amine ligand in accordance with the reaction substrate.
A complex, among the rutheniumhydride complexes expressed by general formula (1), with which the amine ligand is an R, R form, enables preparation of an optically active alcohol compound by chiral reduction of an asymmetric carbonyl compound in a reaction solvent under the non-presence of a strong base and the presence of hydrogen or hydrogen donating compound. Here, though the phosphine ligand may be an R form or an S form, or both forms may coexist (for example as a racemic mixture), an R form or an S form is preferable. The use of either a phosphine ligand of an R form or an S form is preferably selected in accordance with the type of asymmetric carbonyl compound that is the reaction substrate. That is, depending on the type of asymmetric carbonyl compound more favorable results may be obtained if the phosphine ligand is of an R form or more favorable results may be obtained if the phosphine ligand is of an S form, and it is thus preferable to select the steric structure of the phosphine ligand in accordance with the reaction substrate. Further, a complex, among the ruthenium hydride complexes expressed by general formula (1), with which the amine ligand is an S, S form, also enables preparation of an optically active alcohol compound by chiral reduction of an asymmetric carbonyl compound in a reaction solvent under the non-presence of a strong base and the presence of hydrogen or hydrogen donating compound. Here, though the phosphine ligand may be an R form or an S form, or both forms may coexist (for example as a racemic mixture), an R form or an S form is preferable. The use of either an phosphine ligand of an R form or an S form is preferably selected in accordance with the type of asymmetric carbonyl compound that is the reaction substrate. That is, depending on the type of asymmetric carbonyl compound more favorable results may be obtained if the phosphine ligand is of an R form or more favorable results may be obtained if the phosphine ligand is of an S form, and it is thus preferable to select the steric structure of the phosphine ligand in accordance with the reaction substrate.
When a ruthenium hydride complex expressed by general formula (1) is used to prepare an alcohol compound by reduction of an asymmetric carbonyl compound in a reaction solvent under the non-presence of a strong base and the presence of hydrogen or hydrogen donating compound, the asymmetric carbonyl compound may be one that is sensitive to bases. Since a strong base is not made present in this reduction reaction, side reactions besides the carbonyl reduction reaction are less likely to occur even with base-sensitive asymmetric carbonyl compounds. Examples of such base-sensitive asymmetric carbonyl compounds include asymmetric carbonyl compounds, with an ester group, epoxy group, or xcex2-amino group, and xcex1, xcex2-unsaturated ketones, etc. For example, though with an asymmetric carbonyl compound having an ester group, when a reaction is carried out in an alcohol solvent and under the presence of a strong base as in the prior art, there was the problem that an ester exchange reaction, by which the alkoxy part of the ester group is replaced by the solvent alcohol, proceeds as a side reaction, such a problem does not occur with the present invention. Also, in a case where an asymmetric carbonyl compound has an epoxy group, there was the problem that an epoxy ring opening reaction proceeds as a side reaction when a strong base is present as in the prior art, such a problem does not occur with this invention. Furthermore, in a case where an asymmetric carbonyl compound has a xcex2-amino group, there was the problem that elimination of the xcex2-amino group occurs when a strong base is present as in the prior art, such a problem does not occur with this invention. Yet furthermore, in a case of an xcex1, xcex2-unsaturated ketone, such as 3-nonene-2-one, there was the problem that a polymer compound is produced as a side reaction under the presence of a strong base, such a problem does not occur with this invention.
By using a ruthenium hydride complex expressed by general formula (1), one enantiomer, within a mixture of carbonyl compounds consisting of different enantiomers, can be reduced selectively and separated from the other enantiomer, that is, a racemic mixture of carbonyl compounds can be separated in a reaction solvent under the non-presence of a strong base and the presence of hydrogen or hydrogen donating compound. For example, when carbonyl compounds, having a substituent at the xcex1 position and with which the carbon at the xcex1 position is a chiral carbon, are used as the reaction substrate, since one of the compounds with which the xcex1 position is R or S is reduced to an alcohol more rapidly while the other compound remains as a carbonyl compound, optical separation is enabled as a result. Examples of carbonyl compounds, which have a substituent at the xcex1 position and with which the carbon at the xcex1 position is a chiral carbon, include 2-isopropylcyclohexanone, 2-methylcyclohexanone, 2-isopropylcyclopentanone, 2-isopropylcycloheptanone, 2-ethylcyclohexanone, 2-benzylcyclohexanone, 2-allylcyclohexanone, 2-phenylpropiophenone and other ketones having a hydrocarbon group at the xcex1 position, 2-methoxycyclohexanone, 2-ethoxycyclohexanone, 2-isopropyloxycyclohexanone, 2-t-butyloxycyclohexanone, 2-phenoxycyclohexanone, 2-methoxycyclopentanone, 2-methoxycycloheptanone, 2-methoxypropiophenone and other xcex1-alkoxyketones, 2-(dimetylamino)cyclohexanone,2-(methylamino)cyclohexanon, 2-(benzoylmethyl)aminocyclohexanone, 2-(dimethylamino)cyclopentanone, 2-(dimethylamino)cycloheptanone and other xcex1-aminoketones.
[Measurement Instruments and Devices]
For nuclear magnetic resonance (NMR) measurements, JNM-A400 (1HNMR, 400 MHz; 13CNMR, 100 MHz; 3PNMR, 166 MHz), made by JEOL Ltd., was used. For chemical shifts, xcex4 values were expressed in ppm, tetramethylsilane (TMS) was used as an internal standard substance for 1HNMR and 13CNMR, 10% phosphoric acid in deuterium oxide was used as an external standard for 31PNMR, and xcex4=0 was set to the signals of these standards. Coupling constants (J) were expressed in Hz, and with regard to signal splitting modes, a singlet was abbreviated as s, a doublet as d, a triplet as t, a quadruplet as q, a multiplet as m, and a broad line as br. Specific rotations ([xcex1]D) were measured in the indicated solvents and concentrations and using 5 mmxcfx86xc3x975 cm cells in P-1010-GT, made by JASCO Corp. For gas chromatography analysis, measurements by FID using the indicated capillary column and helium pressure were made with 6890,made by Hewlett Packard Inc. For high-performance liquid chromatography analysis, a PU-980 pump, made by JASCO Corp., and a UV-975 UV detector, made by JASCO Corp., were used and measurements were made with the indicated columns, solvents, UV detection wavelengths, and flow rates. Kieselgel 60F254ARt.5715 (0.25 mm thickness), made by Merck and Co., was used for analytical and sampling silica-gel thin-layer chromatography (TLC). Silica Gel 60N (40 to 50 xcexcm), made by Kanto Kagaku Co., Ltd., was used for sampling column chromatography.